Amyotrophic lateral sclerosis (ALS, or Lou Gehrig's disease) is a devastating and fatal neurodegenerative disease. It is characterized by degeneration primarily of motor neurons, atrophy and paralysis of skeletal muscles, and rapid progression to death. Most ALS cases are sporadic and likely caused by environmental factors whereas approximately 5-15% of ALS cases are familial (FALS). The best-studied FALS gene encodes the cytosolic copper-zinc superoxide dismutase (SOD1), missense mutations of which cause up to 20% of FALS cases. The mechanism underlying ALS remains poorly understood and there is no effective treatment for this disease at present. In recent years, transgenic animal models for SOD1-induced ALS have played a significant role in advancing the understanding and treatment of ALS. However, no such a transgenic Drosophila model exists, preventing us from tapping onto the genetic power of this model organism to investigate ALS. To this end, we have generated transgenic flies expressing mutant human SOD1s. Preliminary studies show that these flies recapitulate many features associated with ALS in humans and rodent models, including defects in locomotion and dysfunction of motoneurons. Our immediate goals are to first fully characterize these transgenic flies at cellular, behavioral, and physiological levels to confirm indeed that they have ALS-like defects. Next, we will conduct unbiased genetic modifier screens to identify genes that suppress or enhance flightless in mutant SOD1 transgenic flies to gain insights into the biochemical and molecular pathways involved in ALS. Our long-term objectives are to use genetic, molecular, and electrophysiological approaches in Drosophila to reveal the cellular and molecular mechanisms underlying ALS. This includes the use the ALS fly to screen for potential drugs and environmental factors that alleviate or enhance the mutant phenotype. We believe that the transgenic studies proposed here are complementary to the on-going work in mice and rats and may shed light on not only ALS, but other degenerative diseases as well. This proposal focuses on establishing a fruit fly model for ALS enabling us to better understand the genetic pathways involved in ALS. Hence, the research projects proposed here may have a direct impact on ALS. [unreadable] [unreadable]